Methods for stabilizing a bioprosthetic tissue by chemical modification of antigenic carbohydrates

• US 8,906,601 B2
• Filed: 06/17/2011
• Issued: 12/09/2014
• Est. Priority Date: 06/17/2010
• Status: Active Grant

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Dove, Jeffrey S., Tod, Tara J.
• Primary Examiner(s): Fox, Allison
• Assistant Examiner(s): Pyla, Yvonne
• Application Number:
  US13/163,557
• Publication Number:
  US 20110311493A1
• Time in Patent Office: 1,271 Days
• Field of Search: None
• US Class Current: 435/1.1
• CPC Class Codes: A61L 2430/20 for reconstruction of the heart, e.g. heart valves
• CPC Class Codes: A61L 2430/40 Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
• CPC Class Codes: A61L 27/3687 characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Methods are provided herein for modifying antigenic carbohydrate epitopes within a xenographic bioprosthetic tissue by oxidation of vicinal diols to form aldehydes or acids and subsequence reductive amination of aldehydes to form stable secondary amines, or amidation or esterification of acids to form stable amides or esters. Advantageously, methods provided herein mitigate the antigenicity of the bioprosthetic tissue while leaving the overall tissue structure substantially undisturbed, and thereby enhance the durability, safety and performance of the bioprosthetic implant.

Claims

1. A method for improving the performance of a bioprosthetic implant, the method comprising:

treating a fixed bioprosthetic tissue with an oxidizing agent that selectively oxidizes antigenic carbohydrates having vicinal diols to produce free aldehyde or acid moieties on the antigenic carbohydrate and

treating the bioprosthetic tissue with a capping agent, the capping agent comprising a primary amine or alcohol which combines with the aldehyde or acid to form an imine, amide or ester.

2. The method of claim 1, further comprising treating the bioprosthetic tissue with a stabilizing agent, the agent converting the imine to a secondary amine or the ester to an amide.

3. The method of claim 1, wherein the antigenic carbohydrate is N-glycolylneuraminic acid (Neu5Gc) or the Forssman antigen (GalNAc alpha1,3GalNAc beta1,3Gal alpha1,4Gal beta1,4Glc-Cer).

4. The method of claim 1, wherein the antigenic carbohydrate comprises an α

-galactosyl (α

-Gal) epitope.

5. The method of claim 1, wherein the oxidizing agent is capable of selectively oxidizing the vicinal diol of the antigenic carbohydrate relative to .beta.-aminoalcohol and vicinal diketone groups comprising the bioprosthetic tissue.

6. The method of claim 1, wherein the oxidizing agent is a periodate or acetate.

7. The method of claim 6, wherein the periodate is sodium periodate.

8. The method of claim 7, wherein the sodium periodate is used at a concentration of 20 mM and wherein the bioprosthetic tissue is treated with the sodium periodate for about 4 hours at about 25°

C.

9. The method of claim 1, wherein the capping agent is R⁴-M-NH₂, wherein:

R⁴ is H, C_1-6 alkyl, S(═

O)₂OR⁵, C_1-6 alkoxy, or hydroxyl;

M is a linker, wherein the linker is C_1-6 alkylene; and

R⁵ is H or C_1-6 alkyl.

10. The method of claim 9, wherein the capping agent is an amine, alkyl amine, hydroxylamine, aminoether, amino sulfonate, or a combination thereof.

11. The method of claim 9, wherein R⁴ is C_1-6 alkoxy.

12. The method of claim 9 wherein R⁴ is H.

13. The method of claim 9, wherein R⁴ is S(═

O)₂OR⁵ and R⁵ is H.

14. The method of claim 1, wherein the capping agent is ethanolamine, taurine, ethylamine, or 2-methoxyethylamine.

15. The method of claim 2, wherein the stabilizing agent is a reducing agent.

16. The method of claim 15, wherein the reducing agent is selected from the group consisting of sodium borohydride and sodium cyanoborohydride.

17. The method of claim 1, wherein the bioprosthetic tissue is treated with the oxidizing agent in the presence of the capping agent.

18. The method of claim 1, wherein the bioprosthetic tissue is washed to remove the oxidizing agent prior to treatment with the stabilizing agent.

19. The method of claim 1, wherein the bioprosthetic tissue has been treated with one or more of a surfactant and a fixative agent.

20. The method of claim 19, wherein the fixative agent is selected from the group consisting of an aldehyde, a dialdehyde, a diisocyanate, a carbodiimide, a photooxidation agent, and a polyepoxy compound.

21. The method of claim 19, wherein the surfactant is selected from the group consisting of an anionic surfactant, an alkyl sulfonic acid salt, a polyoxyethylene ether, a pluronic or tetronic surfactant, and an alkylated phenoxypolyethoxy alcohol.

22. The method of claim 19, wherein the bioprosthetic tissue has been treated with glutaraldehyde.

23. The method of claim 19, wherein the bioprosthetic tissue has been treated with a surfactant and a fixative agent.

24. The method of claim 1, wherein the bioprosthetic implant is a heart valve.

25. The method of claim 24, wherein the bioprosthetic tissue is bovine pericardium or porcine aortic valve.

26. The method of claim 25, wherein the bioprosthetic implant is a configured for implantation into a pediatric patient.

27. The method of claim 1, wherein the treated bioprosthetic tissue is substantially non-immunogenic in a human host.

28. The method of claim 1, wherein the antigenic carbohydrate of the treated bioprosthetic tissue is substantially non-antigenic in a human host.

29. The method of claim 1, wherein the treated bioprosthetic tissue is substantially non-calcifying in a human host.

30. The method of claim 29, wherein the human host is a pediatric patient.

31. The method of claim 1, further comprising treating the bioprosthetic tissue with one or more of surfactant and a fixative agent.

32. The method of claim 31, wherein the fixative agent is an aldehyde fixative agent.

33. The method of claim 32, wherein the aldehyde fixative agent is glutaraldehyde.

34. The method of claim 31, wherein the fixative agent is a diacid or a diamine with a carbodiimide (EDC).

35. The method of claim 31, wherein the fixative agent is diepoxy.

36. The method of claim 1, wherein the bioprosthetic tissue is a fresh tissue.

37. The method of claim 1, further comprising treating the bioprosthetic tissue with a bioburden reduction solution comprising formaldehyde, ethanol, and a polyethylene sorbital ester solution.

38. The method of claim 1, further comprising drying the bioprosthetic tissue with ethanol and glycerol.

39. The method of claim 1, further comprising sterilizing the bioprosthetic tissue with ethylene oxide.

40. The method of claim 1, further comprising decellularizing the bioprosthetic tissue with a decellularization method comprising treating the tissue with 0.1% SDS, rinsing the tissue, and treating the tissue with DNAse.

41. The method of claim 1, further comprising drying and electrophoretically cleaning the bioprosthetic tissue.

42. The method of claim 1, further comprising sterilizing the bioprosthetic tissue with glutaraldehyde.

43. The method of claim 1, further comprising treating the bioprosthetic tissue with a bioburden reduction solution comprising ethanol and a polyethylene sorbital ester solution.

44. A method for improving the performance of a bioprosthetic implant, the method comprising the steps of:

obtaining the bioprosthetic tissue, wherein the bioprosthetic tissue is a fresh tissue;

fixing the bioprosthetic tissue with a fixation agent comprising glutaraldehyde;

treating the bioprosthetic tissue with a bioburden reduction solution comprising formaldehyde, ethanol, and a polyethylene sorbital ester solution;

treating the bioprosthetic tissue with an oxidizing agent that selectively oxidizes antigenic carbohydrates having vicinal diols to produce free aldehyde or acid moieties on the antigenic carbohydrate;

treating the bioprosthetic tissue with a capping agent, wherein the capping agent comprises a primary amine or an alcohol, wherein the primary amine interacts with the aldehyde to form an imine, or an acid to form an amide; and

the alcohol interacts with the acid to form an ester;

treating the bioprosthetic tissue with a stabilizing agent, wherein the stabilizing agent interacts with the imine to form a secondary amine and esters to form an amide;

drying the bioprosthetic tissue with ethanol and glycerol; and

sterilizing the bioprosthetic tissue with ethylene oxide.

45. The method of claim 44, wherein the oxidizing agent is a periodate.

46. The method of claim 44, wherein the stabilizing agent is a reducing agent.

47. The method of claim 44, further comprising at least partially fabricating a bioprosthetic product or device from the bioprosthetic tissue using a fabrication device.

48. The method of claim 44, wherein the drying is performed after the fixing and the treating steps.